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1Clinical Laboratory, The First Affiliated Hospital of Wannan Medical College, 241001 Wuhu, Anhui, China
2Department of Pathology, The First Affiliated Hospital of Wannan Medical College, 241001 Wuhu, Anhui, China
*Corresponding Author(s):xuwuqin06@126.com (Wuqin Xu)
| History | Submitted: 04 August 2025 | Accepted: 09 October 2025 | Published: 15 November 2025 |
| Copyright: | ©2025 The Author(s). Published by MRE Press. |
Background: Breast cancer remains one of the most prevalent malignancies among women worldwide, and chemotherapy with paclitaxel (PTX) is a cornerstone of treatment. However, the frequent occurrence of drug resistance significantly limits its clinical efficacy, highlighting the need to identify novel molecular targets involved in chemoresistance. Methods: FK506 Binding Protein 10 (FKBP10) expression was determined in PTX-resistant and non-resistant tissues using quantitative polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry (IHC). PTX-resistant BC cell lines were established, and FKBP10 expression was assessed. The effect of FKBP10 on PTX sensitivity in resistant cell lines was evaluated through Cell Counting Kit-8 (CCK-8) as well as colony formation assays. Autophagy and apoptosis were analyzed using immunoblotting and flow cytometry, while a xenograft model was employed to validate the role of FKBP10 in tumor growth and drug response in vivo. Results: FKBP10 expression was significantly upregulated in PTX-resistant tissues as well as cells. Silencing FKBP10 enhanced cellular sensitivity to PTX, reduced autophagy, and stimulated apoptosis in resistant cells. Mechanistically, FKBP10 was found to regulate the protein kinase B (AKT)/cAMP response element-binding protein (CREB) signaling axis. In vivo, FKBP10 depletion inhibited tumor growth and further increased the sensitivity of tumors to PTX. Conclusions: FKBP10 promoted BC chemosensitivity via inhibiting AKT/CREB-mediated autophagy. Therefore, FKBP10 could serve as a target.
Cite this article
Long Cheng, Xiang Zhu, Zihe Xing, Xiaoning Li, Wuqin Xu. FKBP10 ablation promotes breast cancer chemosensitivity via targeting autophagy and the AKT/CREB axis.European Journal of Gynaecological Oncology,2025,46(11):60-69 DOI:10.22514/ejgo.2025.138
1. Introduction
Breast cancer (BC) is one of the most common women malignancies [1]. Although the mortality rate among BC patients has declined due to advances in early detection and treatment strategies [2, 3], metastasis remains the leading cause of death [4]. Traditional approaches such as surgical resection and chemoradiotherapy have been applied in the treatment of metastatic BC; however, surgical intervention plays only a limited role in advanced disease, and systemic therapies, including chemotherapy and radiotherapy, are frequently hampered by drug resistance and adverse effects, thereby emphasizing the need for more effective therapeutic strategies [5].
A major obstacle in the management of BC is the poor response of many patients to chemotherapy, which is largely attributable to the development of drug resistance [6]. One contributing factor is the overexpression of multidrug resistance protein 1 (MDR1), which mediates resistance to a wide range of chemotherapeutic agents [7]. In addition, alterations in autophagy function have been identified as an important mechanism underlying chemoresistance [8, 9]. For example, the expression of the autophagy-related protein microtubule-associated protein 1 light chain 3 (LC3) is markedly elevated in paclitaxel (PTX)-resistant BC cells [10]. Importantly, inhibition of protective autophagy has been shown to enhance the sensitivity of resistant cells to chemotherapy, including PTX, by promoting apoptotic activity [11].
FK506 Binding Protein 10 (FKBP10) encodes a 65-kD protein, also known as FKBP65, which is vital in collagen biosynthesis and the construction of bone and tendon through the collagen pyridinoline cross-linking pathway [12, 13]. Mutations or loss of function of FKBP10 impair collagen formation, resulting in bone fragility, joint contracture, and severe disorders such as osteogenesis imperfecta and Brooke syndrome [14]. Beyond its physiological role, FKBP10 has been implicated in tumor progression [15, 16]. For instance, FKBP10 regulates protein translation and supports the growth of lung cancer cells through interactions with ribosomes [17]. Moreover, it has been reported to promote the malignant progression of glioma via AKT-CREB-proliferating cell nuclear antigen (PCNA) axis [18].
We aimed to elucidate the role of FKBP10 in the development of resistance to PTX in BC and to further clarify the molecular mechanisms underlying its function.
2. Materials and methods
2.1 Antibodies, shRNAs, and agents
FKBP10 (1:300, ab230852, Abcam, Cambridge, UK), Ki67 (1:100 for IHC, ab15580, Abcam, Cambridge, UK), LC3 (1:1000, ab63817, Abcam, Cambridge, UK), Autophagy related 5 (ATG5) (1:500, ab108327, Abcam, Cambridge, UK), Bcl-2-associated X protein (Bax) (1:500, ab32503, Abcam, Cambridge, UK), B-cell lymphoma 2 (Bcl-2) (1:1000, ab32124, Abcam, Cambridge, UK), Cleaved caspase-3 (1:500, ab32042, Abcam, Cambridge, UK), p-AKT (1:500 for immunoblotting and 1:50 for IHC, ab38449, Abcam, Cambridge, UK), CREB (1:500, ab32515, Abcam, Cambridge, UK), p-CREB (1:500 for immunoblotting and 1:50 for IHC, ab32096, Abcam, Cambridge, UK), and β-actin (1:2000, ab8226, Abcam, Cambridge, UK).
The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay kit (ab206386) was purchased from Abcam (Cambridge, UK). PTX (T7402) was bought from Sigma (St. Louis, MO, USA). The CCK-8 cell viability kit (C0037, Beyotime Biotechnology, Shanghai, China) was used. The Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) apoptosis detection kit (C1062, Beyotime Biotechnology, Shanghai, China) was used for flow cytometry, and the M-MuLV cDNA Synthesis Kit (B532435, Sangon Biotech, Shanghai, China) and FastSYBR Mixture (B638313, Sangon Biotech, Shanghai, China) were used for quantitative PCR (qPCR).
2.2 Patients and samples
BC patients (n = 50) who received PTX (n = 50) according to clinical and pathological standards at The First Affiliated Hospital of Wannan Medical College between March 2024 and March 2025 were included in this study. The age range of the patients was 45 to 80 years. All patients gave informed consent and signed the informed consent form.
2.3 Immunohistochemistry (IHC) staining
Tumor specimens were fixed with 10% neutral buffered formalin for 24 h, embedded in paraffin, and sectioned at 5 µm thickness. Nonspecific binding was blocked with 5% bovine serum albumin (BSA) for 30 min at room temperature. Sections were then incubated with primary antibodies (as listed above) overnight at 4 °C, followed by incubation with horseradish peroxidase (HRP)-conjugated secondary antibody for 30 min. Signals were visualized with 3,3′-diaminobenzidine (DAB) substrate, counterstained with hematoxylin.
2.4 Cell culture and transfection
Human BC cell lines MCF-7 and MDA-MB-231 were obtained from American Type Culture Collection (ATCC) (Manassas, VA, USA). Cells were cultured in Roswell Park Memorial Institute (RPMI)-1640 medium (Gibco, USA) supplemented with 20% fetal bovine serum (FBS). The cultures were maintained at 37 °C. Short hairpin RNAs (shRNAs) targeting FKBP10 were synthesized and cloned into a lentiviral vector (GeneChem, China). Lentiviral particles were generated by co-transfecting HEK293T cells with shRNA plasmids and packaging plasmids or red fluorescent protein (RFP)-LC3 using Lipofectamine 3000 (L3000015, Invitrogen, Carlsbad, CA, USA). Stable cell lines were selected with 2 µg/mL puromycin for 7 days, and knockdown efficiency was confirmed by quantitative reverse transcription (qRT)-PCR and immunoblotting.
2.5 Construction of PTX-resistant BC cells (MCF-7/R and MDA-MB-231/R cells)
MCF-7 and MDA-MB-231 cells were incubated with the IC50 (Half maximal inhibitory concentration) of PTX (0.46 µmol/L for MCF-7 and 0.53 µmol/L for MDA-MB-231) for 4 days, followed by drug-free incubation for three days until normal proliferation resumed. This cycle was repeated six times over approximately 6 weeks, which led to the establishment of PTX-resistant cell lines.
2.6 Quantitative real-time PCR (qRT-PCR)
Total RNA was extracted using TRIzol reagent (15596026, Invitrogen, Carlsbad, CA, USA) following the manufacturer’s instructions. RNA purity and concentration were assessed with a NanoDrop 2000 spectrophotometer (ND-2000, Thermo Scientific, Carlsbad, CA, USA). One microgram of RNA was reverse-transcribed into cDNA using the M-MuLV cDNA Synthesis Kit (B532435, Sangon Biotech, China). Quantitative PCR was performed with FastSYBR Mixture (B638313, Sangon Biotech, China) on an ABI 7500 Real-Time PCR System (7500, Applied Biosystems, Foster City, CA, USA).
2.7 Immunoblotting
Proteins were extracted using radioimmunoprecipitation assay (RIPA) lysis buffer (P0013B, Beyotime, Shanghai, China). Proteins were separated by 8–12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred onto nitrocellulose (NC) membranes (Millipore, USA). Membranes were blocked with 5% fat-free milk for 1 h and then incubated with primary antibodies at 4 °C for 2 h. After washing, membranes were incubated with HRP-conjugated secondary antibodies for 1 h. Protein bands were visualized using enhanced chemiluminescence.
2.8 Cell counting kit-8 (CCK-8) assay
Cell viability was assessed with the CCK-8 (C0037, Beyotime Biotechnology, Shanghai, China). Cell viability was calculated, and IC50 values were determined by nonlinear regression analysis using GraphPad Prism software (9.0, GraphPad Software, Inc., San Diego, CA, USA).
2.9 Flow cytometry (FCM) assay
Apoptosis was evaluated using the Annexin V-FITC/PI Apoptosis Detection Kit (C1062, Beyotime Biotechnology, China). The data were processed using FlowJo software (10.0, BD, Ashland, OR, USA), and apoptotic cells were quantified as the sum of early and late apoptotic populations.
2.10 Xenograft assay
Female BALB/c nude mice (8 weeks old) were used in the xenograft experiments (n = 6 in each group). BC cells transfected with shRNAs were subcutaneously inoculated into the mice. After 32 days, tumors were harvested, and the mice were sacrificed for further analysis.
2.11 Statistical analysis
All statistical analyses were performed using GraphPad Prism software (GraphPad Software, USA). Data were expressed as mean ± standard deviation (SD). Comparisons between groups were conducted using Student’s t-test, and a p-value < 0.05 was thought significant.
3. Results
3.1 FKBP10 was highly expressed in PTX-resistant BC tissues and cells
To investigate the potential role of FKBP10 in PTX resistance in BC, we first examined its expression in PTX-resistant and non-resistant BC tissues collected from our hospital. qPCR analysis revealed significantly elevated mRNA levels of FKBP10 in PTX-resistant tissues (Fig. 1A). Consistently, both immunoblotting and IHC demonstrated markedly higher FKBP10 protein expression in PTX-resistant tissues (Fig. 1B,C).
We subsequently established PTX-resistant BC cell lines and determined their IC50 values in response to PTX. The IC50 values of MCF-7 as well as MCF7/R cells were 0.47 ± 0.033 and 4.05 ± 0.294 µmol/L, respectively, while those of MDA-MB-231 as well as MDA-MB-231/R cells were 0.54 ± 0.042 and 4.54 ± 0.381 µmol/L, respectively (Fig. 1D). These findings confirmed the successful establishment of PTX-resistant BC cell models.
To further evaluate FKBP10 expression in these resistant cells, we performed qPCR and immunoblot assays. We observed that FKBP10 mRNA levels were upregulated in PTX-resistant MCF-7 and MDA-MB-231 cells (Fig. 1E). Consistently, immunoblot analysis revealed markedly higher FKBP10 protein expression in resistant cells (Fig. 1F). Moreover, survival analysis indicated that high FKBP10 expression was associated with unfavorable prognosis in BC patients (Fig. 1G). Collectively, these results demonstrated that FKBP10 was highly expressed in PTX-resistant BC tissues and cells.
Fig. 1.FKBP10 was highly expressed in paclitaxel (PTX)-resistant breast cancer tissues and cells. (A) qPCR analysis of FKBP10 mRNA levels in PTX-resistant and non-resistant BC tissues. (B) Immunoblot analysis of FKBP10 protein levels in PTX-resistant and non-resistant BC tissues. (C) IHC staining of FKBP10 expression in PTX-resistant and non-resistant BC tissues. (D) CCK-8 assays showing the IC50 values of MCF-7 and MDA-MB-231 cell lines treated with PTX at the indicated concentrations. (E) qPCR analysis of FKBP10 mRNA levels in PTX-resistant and non-resistant MCF-7 and MDA-MB-231 cells. (F) Immunoblot analysis of FKBP10 protein levels in PTX-resistant and non-resistant MCF-7 and MDA-MB-231 cells. (G) Prognostic analysis of BC patients stratified by high or low FKBP10 expression. Each experiment was repeated three times. Data are shown as mean ± SD, ***p < 0.001. FKBP10: FK506 Binding Protein 10; PTX: paclitaxel; IC50: half maximal inhibitory concentration.
3.2 FKBP10 depletion enhanced the sensitivity of BC cells to PTX
We next assessed the functional role of FKBP10 in mediating PTX resistance. FKBP10 expression was silenced in resistant cells using shRNAs, which efficiently reduced FKBP10 protein levels (Fig. 2A). CCK-8 assays revealed that FKBP10 knockdown markedly decreased the IC50 values of PTX in resistant cells: from 4.01 ± 0.407 to 1.02 ± 0.106 µmol/L in MCF-7/R cells, and from 4.55 ± 0.447 to 1.25 ± 0.111 µmol/L in MDA-MB-231/R cells (Fig. 2B).
FKBP10 depletion suppressed the proliferative capacity of both resistant cell lines. Importantly, when combined with PTX treatment, FKBP10 knockdown exerted an even stronger inhibitory effect on colony formation (Fig. 2C). Immunoblotting confirmed that FKBP10 expression was effectively silenced by shRNA but restored upon co-transfection with FKBP10 plasmids in both resistant cell lines (Fig. 2D). Functionally, CCK-8 assays showed that FKBP10 knockdown significantly reduced the IC50 values of PTX in resistant cells, thereby enhancing chemosensitivity, whereas re-expression of FKBP10 rescued this effect and restored drug resistance (Fig. 2E). Similarly, colony formation assays revealed that silencing FKBP10 markedly suppressed clonogenic growth, while re-expression partially restored the colony formation ability (Fig. 2F). Taken together, these results demonstrated that FKBP10 depletion significantly enhanced the sensitivity of BC cells to PTX.
Fig. 2.FKBP10 depletion enhanced the sensitivity of BC cells to PTX. (A) Immunoblot analysis of FKBP10 protein levels in PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. (B) CCK-8 assays showing the IC50 values of PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. (C) Colony formation assays assessing the proliferative capacity of PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. (D) Immunoblot analysis of FKBP10 expression in MCF-7/R and MDA-MB-231/R cells transfected with shNC, shFKBP10, or shFKBP10 + FKBP10; quantification of FKBP10 protein levels is shown on the right. (E) CCK-8 assays showing IC50 values of PTX in MCF-7/R and MDA-MB-231/R cells after FKBP10 knockdown or rescue. Restoring FKBP10 expression reversed the enhanced chemosensitivity induced by FKBP10 depletion. (F) Colony formation assays showing that reintroduction of FKBP10 partially restored the proliferative capacity of MCF-7/R and MDA-MB-231/R cells suppressed by FKBP10 depletion; quantitative analysis of colony numbers is presented. Each experiment was repeated three times. Data are shown as mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001. FKBP10: FK506 Binding Protein 10; PTX: paclitaxel; IC50: half maximal inhibitory concentration; shNC: short hairpin negative control.
3.3 Depletion of FKBP10 suppressed autophagy in PTX-resistant BC cells
Given that FKBP10 influenced the sensitivity of PTX-resistant BC cells, we examined whether it also affected autophagy. The ratio of LC3II/LC3I was found to be elevated in both MCF-7/R as well as MDA-MB-231/R cells, and ATG5 expression was also increased, indicating enhanced autophagy in resistant cells (Fig. 3A). We then assessed the effect of FKBP10 silencing on these autophagy markers and observed that FKBP10 depletion significantly reduced the LC3II/LC3I ratio and ATG5 expression in resistant cells (Fig. 3B). Consistent with this, RFP-LC3 transfection demonstrated that FKBP10 knockdown inhibited autophagosome formation in PTX-resistant BC cells (Fig. 3C). Moreover, flow cytometry assays showed that FKBP10 depletion promoted apoptosis, whereas treatment with rapamycin, an autophagy inducer, attenuated the pro-apoptotic effect of FKBP10 knockdown (Fig. 3D). These findings indicated that FKBP10 depletion suppressed autophagy in PTX-resistant BC cells.
Fig. 3.Depletion of FKBP10 suppressed autophagy in PTX-resistant breast cancer cells. (A) Immunoblot analysis of LC3II, LC3I, and ATG5 expression in PTX-resistant and non-resistant MCF-7 and MDA-MB-231 cells. (B) Immunoblot analysis of LC3II, LC3I, and ATG5 expression in PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. (C) RFP-LC3 fluorescence intensity in MDA-MB-231 cells under the indicated treatments. (D) Flow cytometry analysis of apoptosis rates in MDA-MB-231 cells under the indicated treatments. Each experiment was repeated three times. Data are shown as mean ± SD, **p < 0.01, ***p < 0.001. FKBP10: FK506 Binding Protein 10; LC3: microtubule-associated protein 1 light chain 3; ATG5: autophagy related 5; shNC: short hairpin negative control; RFP: red fluorescent protein; DAPI: 4′,6-diamidino-2-phenylindole; PI: propidium iodide; FITC: fluorescein isothiocyanate.
3.4 FKBP10 ablation stimulated apoptosis in PTX-resistant BC cells
We further investigated the impact of FKBP10 on apoptosis in resistant cells. Flow cytometry demonstrated that FKBP10 depletion increased apoptosis in both MCF-7/R and MDA-MB-231/R cells, and this effect was more pronounced in the presence of PTX (Fig. 4A).
Immunoblot analysis revealed that FKBP10 knockdown upregulated Bax and cleaved caspase-3, while downregulating Bcl-2, in resistant cells both with and without PTX treatment (Fig. 4B). These results suggested that FKBP10 ablation promoted apoptosis in PTX-resistant BC cells.
Fig. 4.FKBP10 ablation stimulated apoptosis in PTX-resistant breast cancer cells. (A) Flow cytometry analysis of apoptosis in PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. (B) Immunoblot analysis of Bax, Bcl-2, and cleaved caspase-3 expression in PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. Each experiment was repeated three times. Data are shown as mean ± SD, *p < 0.05, **p < 0.01, ***p < 0.001. FKBP10: FK506 Binding Protein 10; PTX: paclitaxel; shNC: short hairpin negative control; PI: propidium iodide; FITC: fluorescein isothiocyanate; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2.
3.5 FKBP10 mediated the AKT/CREB axis in PTX-resistant BC cells
As previous studies had implicated FKBP10 in the regulation of the AKT/CREB axis [18], we investigated whether this pathway was also involved in PTX resistance. Immunoblot analysis revealed that FKBP10 depletion decreased the phosphorylation levels of both AKT and CREB in resistant cells (Fig. 5). These findings suggested that FKBP10 mediates autophagy and survival signaling in PTX-resistant BC cells via AKT/CREB axis.
Fig. 5.FKBP10 mediated the AKT/CREB axis in PTX-resistant breast cancer cells. Immunoblot analysis of AKT, CREB, and their phosphorylated forms (p-AKT and p-CREB) in PTX-resistant MCF-7 and MDA-MB-231 cells under the indicated treatments. Each experiment was repeated three times. Data are shown as mean ± SD, **p < 0.01, ***p < 0.001. FKBP10: FK506 Binding Protein 10; AKT: protein kinase B; CREB: cAMP response element-binding protein; shNC: short hairpin negative control.
3.6 FKBP10 knockdown inhibited tumor growth and enhanced PTX sensitivity in vivo
To validate the role of FKBP10 in vivo, xenograft experiments were conducted using MCF-7/R cells. Tumor growth was significantly slower in the FKBP10 shRNA group than in controls (Fig. 6A). Moreover, PTX treatment (25 mg/kg) further reduced tumor growth in FKBP10-depleted mice (Fig. 6A). IHC analysis of tumor specimens showed that FKBP10 depletion decreased Ki67 expression and reduced phosphorylation of AKT and CREB, while increasing TUNEL-positive cells (Fig. 6B). PTX administration in FKBP10-depleted tumors further enhanced these effects, with greater suppression of Ki67, p-AKT, and p-CREB, as well as increased apoptosis (Fig. 6B). These results demonstrated that FKBP10 knockdown inhibited BC tumor growth and enhanced PTX sensitivity in vivo.
Fig. 6.FKBP10 knockdown inhibited tumor growth and increased PTX sensitivity in vivo. (A) Xenograft assays showing differences in tumor growth and tumor weight among the indicated groups. (B) IHC staining of Ki67, TUNEL, p-AKT, and p-CREB in tumor tissues from the indicated groups. Each experiment was repeated three times. Data are shown as mean ± SEM, *p < 0.05, ***p < 0.001. FKBP10: FK506 Binding Protein 10; PTX: paclitaxel; shNC: short hairpin negative control; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; AKT: protein kinase B; CREB: cAMP response element-binding protein.
4. Discussion
PTX is a first-line chemotherapeutic agent for the treatment of BC; however, a subset of patients exhibits poor sensitivity to PTX [19]. Clinical observations have shown that the expression level of estrogen receptor α (ERα) in BC tissues is significantly correlated with the response to PTX-based chemotherapy, although the underlying mechanisms remain unclear [20]. Therefore, chemotherapy resistance represents a major barrier to effective treatment, and elucidating its molecular basis is essential for improving clinical outcomes. Among the mechanisms implicated in resistance, increasing evidence has highlighted a close association between autophagy and chemotherapeutic response in BC [21]. In particular, LC3 expression, which reflects the extent of autophagy, has been shown to be markedly higher in PTX-resistant BC cells than in sensitive cell lines [22]. On this basis, the present study investigated the role of FKBP10 in PTX resistance. The findings demonstrated that FKBP10 knockdown enhanced chemosensitivity by suppressing AKT/CREB-mediated autophagy, thereby promoting apoptosis, and improving the therapeutic response to PTX.
qPCR, immunoblotting, and IHC assays demonstrated that FKBP10 was highly expressed in PTX-resistant BC tissues and cells. We further confirmed its role in modulating the sensitivity of BC cells to PTX. In addition, immunoblotting and flow cytometry showed that FKBP10 regulated both autophagy and apoptosis in resistant cells. Collectively, these findings indicated that FKBP10 played a central role in reducing chemosensitivity in BC. The involvement of FKBP10 in cancer progression has been widely reported [17, 18]. By interacting with ribosomes, FKBP10 regulates protein translation and sustains lung cancer cell growth [16, 17]. It is also overexpressed in gastric cancer, where it functions as a cancer-promoting marker [16]. Furthermore, FKBP10 has been shown to drive glioma progression through activation of the AKT-CREB-PCNA axis [18]. The present study revealed that FKBP10 knockdown enhanced chemosensitivity in BC by suppressing autophagy through the AKT/CREB pathway.
A quantitative proteomics study reported a strong correlation between FKBP10 expression and glycoproteins associated with multidrug resistance, suggesting that FKBP10 contributes to both the acquisition and maintenance of chemotherapeutic resistance in cancer cells [23]. Analysis of The Cancer Genome Atlas (TCGA) datasets further demonstrated that FKBP10 is significantly overexpressed in BC, supporting the hypothesis that FKBP10 participates in the regulation of BC progression. In addition, FKBP10 has been shown to regulate the phosphoinositide 3-kinase (PI3K)/AKT pathway and its downstream effector CREB [18]. Since CREB activation has been linked to enhanced drug resistance in BC cells [24], this pathway may represent a key mechanism by which FKBP10 modulates therapeutic response. Supporting this, another study demonstrated that FKBP10 promotes chemoresistance by inducing ATG7-regulated autophagy [25]. Consistent with these findings, the present study confirmed that FKBP10 regulates autophagy in BC cells through the AKT/CREB axis. Nevertheless, the precise mechanism remains to be clarified. It is conceivable that FKBP10 may promote AKT phosphorylation either by modulating PI3K activity or through interactions with upstream regulatory proteins, an aspect that warrants further mechanistic investigation in BC models.
Consistent with previous reports showing that FKBP10 promotes glioma progression through the AKT/CREB axis, our findings demonstrate that FKBP10 similarly sustains autophagy and chemoresistance in BC via this pathway. These results underscore the PI3K/AKT/CREB signaling cascade as a pivotal mediator connecting FKBP10 expression to drug resistance, thereby suggesting that therapeutic targeting of this axis may improve treatment efficacy.
The AKT/CREB pathway has been widely implicated in regulating autophagy across different cell types [26, 27]. For example, activation of this pathway has been shown to mediate the neuroprotective effects of nimodipine by promoting autophagy [28]. Moreover, numerous proteins and small molecules, such as resveratrol, have been shown to regulate autophagy through AKT/CREB signaling, thereby influencing diverse pathological processes [29].
This study had several limitations that should be clarified. First, although our findings indicate that FKBP10 is broadly associated with PTX resistance in BC, the potential correlation with ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status remains uncertain. Larger patient cohorts will be required to clarify whether FKBP10 exerts subtype-specific effects that could refine its clinical applicability. Second, while our experimental data establish a link between FKBP10 and the AKT/CREB-mediated autophagy pathway, the precise molecular mechanism remains incompletely defined. Structural modeling and molecular dynamics studies may be necessary to elucidate how FKBP10 directly interacts with components of this signaling cascade. Third, our study did not address the upstream regulatory signals or large-scale molecular networks controlling FKBP10 expression. Future investigations should explore these factors, as they may provide additional insight into the broader role of FKBP10 in BC chemoresistance.
5. Conclusions
FKBP10 was found to be highly expressed in PTX-resistant BC tissues and cells. Knockdown of FKBP10 enhanced chemosensitivity by suppressing AKT/CREB-mediated autophagy and promoting apoptosis. FKBP10 may represent a target for overcoming PTX resistance in BC.
Availability of data and materials
The authors declare that all data supporting the findings of this study are available within the paper and any raw data can be obtained from the corresponding author upon request.
Author contributions
LC—designed the study and carried them out. LC, XZ, ZHX, XNL—supervised the data collection, analyzed the data. LC, XZ, ZHX—interpreted the data. LC, WQX—prepared the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.
Ethics approval and consent to participate
All animal experiments were approved by Wannan Medical College Experimental Animal Welfare and Ethics Committee (Approval No.: WNMC-AWE-20243372). All studies involving human participants were approved by the Medical Ethics Committee of Wannan Medical College (No. 202). Written informed consent was obtained from legally authorized representatives for anonymized patient information to be published in this article.
Acknowledgment
Not applicable.
Funding
This work was supported by Wuhu Science and Technology Program (2024kj055) and Natural Science Foundation of Anhui Provincial Education Department (2024AH051880).
Conflict of interest
The authors declare no conflict of interest.
